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Results: 1 to 10 of 29

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Nanotechnology Enabled Modulation of Signaling Pathways Affects Physiologic Responses in Intact Vascular Tissue.
Hocking KM, Evans BC, Komalavilas P, Cheung-Flynn J, Duvall CL, Brophy CM
(2019) Tissue Eng Part A 25: 416-426
MeSH Terms: Actin Cytoskeleton, Actins, Animals, Blood Vessels, Calcium, Gene Silencing, Heat-Shock Proteins, Humans, Micelles, Muscle Contraction, Muscle, Smooth, Nanoparticles, Nanotechnology, Peptides, Polymerization, RNA, Small Interfering, Rats, Signal Transduction, Static Electricity
Show Abstract · Added April 10, 2019
IMPACT STATEMENT - Subarachnoid hemorrhage (SAH) is associated with vasospasm that is refractory to traditional vasodilators, and inhibition of vasospasm after SAH remains a large unmet clinical need. SAH causes changes in the phosphorylation state of the small heat shock proteins (HSPs), HSP20 and HSP27, in the vasospastic vessels. In this study, the levels of HSP27 and HSP20 were manipulated using nanotechnology to mimic the intracellular phenotype of SAH-induced vasospasm, and the effect of this manipulation was tested on vasomotor responses in intact tissues. This work provides insight into potential therapeutic targets for the development of more effective treatments for SAH induced vasospasm.
0 Communities
1 Members
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19 MeSH Terms
De novo designed transmembrane peptides activating the α5β1 integrin.
Mravic M, Hu H, Lu Z, Bennett JS, Sanders CR, Orr AW, DeGrado WF
(2018) Protein Eng Des Sel 31: 181-190
MeSH Terms: Amino Acid Sequence, Cell Membrane, Computer-Aided Design, Drug Design, Humans, Integrin alpha5beta1, Micelles, Peptides, Protein Conformation, alpha-Helical, Protein Domains
Show Abstract · Added November 21, 2018
Computationally designed transmembrane α-helical peptides (CHAMP) have been used to compete for helix-helix interactions within the membrane, enabling the ability to probe the activation of the integrins αIIbβ3 and αvβ3. Here, this method is extended towards the design of CHAMP peptides that inhibit the association of the α5β1 transmembrane (TM) domains, targeting the Ala-X3-Gly motif within α5. Our previous design algorithm was performed alongside a new workflow implemented within the widely used Rosetta molecular modeling suite. Peptides from each computational approach activated integrin α5β1 but not αVβ3 in human endothelial cells. Two CHAMP peptides were shown to directly associate with an α5 TM domain peptide in detergent micelles to a similar degree as a β1 TM peptide does. By solution-state nuclear magnetic resonance, one of these CHAMP peptides was shown to bind primarily the integrin β1 TM domain, which itself has a Gly-X3-Gly motif. The second peptide associated modestly with both α5 and β1 constructs, with slight preference for α5. Although the design goal was not fully realized, this work characterizes novel CHAMP peptides activating α5β1 that can serve as useful reagents for probing integrin biology.
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10 MeSH Terms
Dodecyl-β-melibioside Detergent Micelles as a Medium for Membrane Proteins.
Hutchison JM, Lu Z, Li GC, Travis B, Mittal R, Deatherage CL, Sanders CR
(2017) Biochemistry 56: 5481-5484
MeSH Terms: Amyloid beta-Protein Precursor, Detergents, Diacylglycerol Kinase, Disaccharides, Dynamic Light Scattering, Enzyme Stability, Escherichia coli Proteins, Glucosides, Glycolipids, Hot Temperature, Humans, Micelles, Myelin Proteins, Nuclear Magnetic Resonance, Biomolecular, Particle Size, Peptide Fragments, Protein Interaction Domains and Motifs, Protein Stability, Receptor, Notch1
Show Abstract · Added November 21, 2018
There remains a need for new non-ionic detergents that are suitable for use in biochemical and biophysical studies of membrane proteins. Here we explore the properties of n-dodecyl-β-melibioside (β-DDMB) micelles as a medium for membrane proteins. Melibiose is d-galactose-α(1→6)-d-glucose. Light scattering showed the β-DDMB micelle to be roughly 30 kDa smaller than micelles formed by the commonly used n-dodecyl-β-maltoside (β-DDM). β-DDMB stabilized diacylglycerol kinase (DAGK) against thermal inactivation. Moreover, activity assays conducted using aliquots of DAGK purified into β-DDMB yielded activities that were 40% higher than those of DAGK purified into β-DDM. β-DDMB yielded similar or better TROSY-HSQC NMR spectra for two single-pass membrane proteins and the tetraspan membrane protein peripheral myelin protein 22. β-DDMB appears be a useful addition to the toolbox of non-ionic detergents available for membrane protein research.
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MeSH Terms
A pH-Mediated Topological Switch within the N-Terminal Domain of Human Caveolin-3.
Kim JH, Schlebach JP, Lu Z, Peng D, Reasoner KC, Sanders CR
(2016) Biophys J 110: 2475-2485
MeSH Terms: Amino Acid Sequence, Caveolin 3, Circular Dichroism, Humans, Hydrogen-Ion Concentration, Membranes, Artificial, Micelles, Models, Molecular, Mutation, Nuclear Magnetic Resonance, Biomolecular, Phosphatidylglycerols, Protein Structure, Secondary, Solubility, Solutions
Show Abstract · Added November 21, 2018
Caveolins mediate the formation of caveolae, which are small omega-shaped membrane invaginations involved in a variety of cellular processes. There are three caveolin isoforms, the third of which (Cav3) is expressed in smooth and skeletal muscles. Mutations in Cav3 cause a variety of human muscular diseases. In this work, we characterize the secondary structure, dynamics, and topology of the monomeric form of the full-length lipidated protein. Cav3 consists of a series of membrane-embedded or surface-associated helical elements connected by extramembrane connecting loops or disordered domains. Our results also reveal that the N-terminal domain undergoes a large scale pH-mediated topological rearrangement between soluble and membrane-anchored forms. Considering that roughly one-third of pathogenic mutations in Cav3 influence charged residues located in this domain, we hypothesize that this transition is likely to be relevant to the molecular basis of Cav3-linked diseases. These results provide insight into the structure of Cav3 and set the stage for mechanistic investigations of the effects of pathogenic mutations.
Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Particle-based technologies for osteoarthritis detection and therapy.
Kavanaugh TE, Werfel TA, Cho H, Hasty KA, Duvall CL
(2016) Drug Deliv Transl Res 6: 132-47
MeSH Terms: Animals, Cell-Derived Microparticles, Delayed-Action Preparations, Dendrimers, Drug Delivery Systems, Humans, Liposomes, Micelles, Nanoparticles, Osteoarthritis
Show Abstract · Added March 14, 2018
Osteoarthritis (OA) is a disease characterized by degradation of joints with the development of painful osteophytes in the surrounding tissues. Currently, there are a limited number of treatments for this disease, and many of these only provide temporary, palliative relief. In this review, we discuss particle-based drug delivery systems that can provide targeted and sustained delivery of imaging and therapeutic agents to OA-affected sites. We focus on technologies such as polymeric micelles and nano-/microparticles, liposomes, and dendrimers for their potential treatment and/or diagnosis of OA. Several promising studies are highlighted, motivating the continued development of delivery technologies to improve treatments for OA.
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10 MeSH Terms
Tuning PEGylation of mixed micelles to overcome intracellular and systemic siRNA delivery barriers.
Miteva M, Kirkbride KC, Kilchrist KV, Werfel TA, Li H, Nelson CE, Gupta MK, Giorgio TD, Duvall CL
(2015) Biomaterials 38: 97-107
MeSH Terms: Animals, Diffusion, Drug Compounding, Humans, Methacrylates, Mice, Mice, Inbred BALB C, Micelles, Nanocapsules, Particle Size, Polyethylene Glycols, RNA, Small Interfering, Subcellular Fractions
Show Abstract · Added March 14, 2018
A series of endosomolytic mixed micelles was synthesized from two diblock polymers, poly[ethylene glycol-b-(dimethylaminoethyl methacrylate-co-propylacrylic acid-co-butyl methacrylate)] (PEG-b-pDPB) and poly[dimethylaminoethyl methacrylate-b-(dimethylaminoethyl methacrylate-co-propylacrylic acid-co-butyl methacrylate)] (pD-b-pDPB), and used to determine the impact of both surface PEG density and PEG molecular weight on overcoming both intracellular and systemic siRNA delivery barriers. As expected, the percent PEG composition and PEG molecular weight in the corona had an inverse relationship with mixed micelle zeta potential and rate of cellular internalization. Although mixed micelles were internalized more slowly, they generally produced similar gene silencing bioactivity (∼ 80% or greater) in MDA-MB-231 breast cancer cells as the micelles containing no PEG (100 D/no PEG). The mechanistic explanation for the potent bioactivity of the promising 50 mol% PEG-b-DPB/50 mol% pD-b-pDPB (50 D) mixed micelle formulation, despite its relatively low rate of cellular internalization, was further investigated as a function of PEG molecular weight (5 k, 10 k, or 20 k PEG). Results indicated that, although larger molecular weight PEG decreased cellular internalization, it improved cytoplasmic bioavailability due to increased intracellular unpackaging (quantitatively measured via FRET) and endosomal release. When delivered intravenously in vivo, 50 D mixed micelles with a larger molecular weight PEG in the corona also demonstrated significantly improved blood circulation half-life (17.8 min for 20 k PEG micelles vs. 4.6 min for 5 kDa PEG micelles) and a 4-fold decrease in lung accumulation. These studies provide new mechanistic insights into the functional effects of mixed micelle-based approaches to nanocarrier surface PEGylation. Furthermore, the ideal mixed micelle formulation identified (50 D/20 k PEG) demonstrated desirable intracellular and systemic pharmacokinetics and thus has strong potential for in vivo therapeutic use.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Cell protective, ABC triblock polymer-based thermoresponsive hydrogels with ROS-triggered degradation and drug release.
Gupta MK, Martin JR, Werfel TA, Shen T, Page JM, Duvall CL
(2014) J Am Chem Soc 136: 14896-902
MeSH Terms: Acrylamides, Acrylic Resins, Animals, Biocompatible Materials, Drug Carriers, Drug Liberation, Hydrogels, Mice, Micelles, Models, Molecular, Molecular Conformation, NIH 3T3 Cells, Oxazines, Polymers, Reactive Oxygen Species, Rheology, Sulfides, Temperature
Show Abstract · Added March 14, 2018
A combination of anionic and RAFT polymerization was used to synthesize an ABC triblock polymer poly[(propylenesulfide)-block-(N,N-dimethylacrylamide)-block-(N-isopropylacrylamide)] (PPS-b-PDMA-b-PNIPAAM) that forms physically cross-linked hydrogels when transitioned from ambient to physiologic temperature and that incorporates mechanisms for reactive oxygen species (ROS) triggered degradation and drug release. At ambient temperature (25 °C), PPS-b-PDMA-b-PNIPAAM assembled into 66 ± 32 nm micelles comprising a hydrophobic PPS core and PNIPAAM on the outer corona. Upon heating to physiologic temperature (37 °C), which exceeds the lower critical solution temperature (LCST) of PNIPAAM, micelle solutions (at ≥2.5 wt %) sharply transitioned into stable, hydrated gels. Temperature-dependent rheology indicated that the equilibrium storage moduli (G') of hydrogels at 2.5, 5.0, and 7.5 wt % were 20, 380, and 850 Pa, respectively. The PPS-b-PDMA-b-PNIPAAM micelles were preloaded with the model drug Nile red, and the resulting hydrogels demonstrated ROS-dependent drug release. Likewise, exposure to the peroxynitrite generator SIN-1 degraded the mechanical properties of the hydrogels. The hydrogels were cytocompatible in vitro and were demonstrated to have utility for cell encapsulation and delivery. These hydrogels also possessed inherent cell-protective properties and reduced ROS-mediated cellular death in vitro. Subcutaneously injected PPS-b-PDMA-b-PNIPAAM polymer solutions formed stable hydrogels that sustained local release of the model drug Nile red for 14 days in vivo. These collective data demonstrate the potential use of PPS-b-PDMA-b-PNIPAAM as an injectable, cyto-protective hydrogel that overcomes conventional PNIPAAM hydrogel limitations such as syneresis, lack of degradability, and lack of inherent drug loading and environmentally responsive release mechanisms.
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18 MeSH Terms
Impact of bilayer lipid composition on the structure and topology of the transmembrane amyloid precursor C99 protein.
Song Y, Mittendorf KF, Lu Z, Sanders CR
(2014) J Am Chem Soc 136: 4093-6
MeSH Terms: Amyloid beta-Protein Precursor, Humans, Lipid Bilayers, Micelles, Nuclear Magnetic Resonance, Biomolecular, Peptide Fragments
Show Abstract · Added November 21, 2018
C99 (also known as β-CTF) is the 99 residue transmembrane C-terminal domain (residues 672-770) of the amyloid precursor protein and is the immediate precursor of the amyloid-β (Aβ) polypeptides. To test the dependence of the C99 structure on the composition of the host model membranes, NMR studies of C99 were conducted both in anionic lyso-myristoylphosphatidylglycerol (LMPG) micelles and in a series of five zwitterionic bicelle compositions involving phosphatidylcholine and sphingomyelin in which the acyl chain lengths of these lipid components varied from 14 to 24 carbons. Some of these mixtures are reported for the first time in this work and should be of broad utility in membrane protein research. The site-specific backbone (15)N and (1)H chemical shifts for C99 in LMPG and in all five bicelle mixtures were seen to be remarkably similar, indicating little dependence of the backbone structure of C99 on the composition of the host model membrane. However, the length of the transmembrane span was seen to vary in a manner that alters the positioning of the γ-secretase cleavage sites with respect to the center of the bilayer. This observation may contribute to the known dependency of the Aβ42-to-Aβ40 production ratio on both membrane thickness and the length of the C99 transmembrane domain.
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MeSH Terms
Reversible folding of human peripheral myelin protein 22, a tetraspan membrane protein.
Schlebach JP, Peng D, Kroncke BM, Mittendorf KF, Narayan M, Carter BD, Sanders CR
(2013) Biochemistry 52: 3229-41
MeSH Terms: Circular Dichroism, Cross-Linking Reagents, Glycerol, Humans, Kinetics, Micelles, Models, Molecular, Myelin Proteins, Protein Conformation, Protein Folding, Protein Stability, Protein Structure, Quaternary, Thermodynamics, Unfolded Protein Response
Show Abstract · Added March 5, 2014
Misfolding of the α-helical membrane protein peripheral myelin protein 22 (PMP22) has been implicated in the pathogenesis of the common neurodegenerative disease known as Charcot-Marie-Tooth disease (CMTD) and also several other related peripheral neuropathies. Emerging evidence suggests that the propensity of PMP22 to misfold in the cell may be due to an intrinsic lack of conformational stability. Therefore, quantitative studies of the conformational equilibrium of PMP22 are needed to gain insight into the molecular basis of CMTD. In this work, we have investigated the folding and unfolding of wild type (WT) human PMP22 in mixed micelles. Both kinetic and thermodynamic measurements demonstrate that the denaturation of PMP22 by n-lauroyl sarcosine (LS) in dodecylphosphocholine (DPC) micelles is reversible. Assessment of the conformational equilibrium indicates that a significant fraction of unfolded PMP22 persists even in the absence of the denaturing detergent. However, we find the stability of PMP22 is increased by glycerol, which facilitates quantitation of thermodynamic parameters. To our knowledge, this work represents the first report of reversible unfolding of a eukaryotic multispan membrane protein. The results indicate that WT PMP22 possesses minimal conformational stability in micelles, which parallels its poor folding efficiency in the endoplasmic reticulum. Folding equilibrium measurements for PMP22 in micelles may provide an approach to assess the effects of cellular metabolites or potential therapeutic agents on its stability. Furthermore, these results pave the way for future investigation of the effects of pathogenic mutations on the conformational equilibrium of PMP22.
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14 MeSH Terms
Macrophage-specific RNA interference targeting via "click", mannosylated polymeric micelles.
Yu SS, Lau CM, Barham WJ, Onishko HM, Nelson CE, Li H, Smith CA, Yull FE, Duvall CL, Giorgio TD
(2013) Mol Pharm 10: 975-87
MeSH Terms: Animals, Cells, Cultured, Click Chemistry, Dendritic Cells, Flow Cytometry, Humans, Lectins, C-Type, Macrophages, Mannose-Binding Lectins, Micelles, Microscopy, Confocal, Nanoparticles, Polymers, RNA Interference, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Receptors, Cell Surface
Show Abstract · Added August 29, 2013
Macrophages represent an important therapeutic target, because their activity has been implicated in the progression of debilitating diseases such as cancer and atherosclerosis. In this work, we designed and characterized pH-responsive polymeric micelles that were mannosylated using "click" chemistry to achieve CD206 (mannose receptor)-targeted siRNA delivery. CD206 is primarily expressed on macrophages and dendritic cells and upregulated in tumor-associated macrophages, a potentially useful target for cancer therapy. The mannosylated nanoparticles improved the delivery of siRNA into primary macrophages by 4-fold relative to the delivery of a nontargeted version of the same carrier (p < 0.01). Further, treatment for 24 h with the mannose-targeted siRNA carriers achieved 87 ± 10% knockdown of a model gene in primary macrophages, a cell type that is typically difficult to transfect. Finally, these nanoparticles were also avidly recognized and internalized by human macrophages and facilitated the delivery of 13-fold more siRNA into these cells than into model breast cancer cell lines. We anticipate that these mannose receptor-targeted, endosomolytic siRNA delivery nanoparticles will become an enabling technology for targeting macrophage activity in various diseases, especially those in which CD206 is upregulated in macrophages present within the pathologic site. This work also establishes a generalizable platform that could be applied for "click" functionalization with other targeting ligands to direct siRNA delivery.
2 Communities
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17 MeSH Terms